Current and new pharmacotherapy options for non-alcoholic steatohepatitis

ABSTRACT

Introduction

There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis.

Areas covered

The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies.

Expert opinion

Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid β receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1–3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.

KEYWORDS:

• Apoptosis signaling kinase 1
• farnesoid X receptor ligand
• fibroblast growth factor
• hepatic fibrosis
• peroxisome proliferator-activated receptor
• glucagon like peptide 1

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Correction

Article highlights

• Currently recommended therapies for NASH are vitamin E and/or pioglitazone, which are not Federal Drug Administration or European Medicines Agency approved therapies.

• Given that the hepatic fibrosis stage is the most important determinant of mortality/morbidity in NASH patients, there is an unmet medical need for an effective anti-fibrotic treatment for those with advanced fibrosis.

• Four drugs, including farnesoid X receptor (FXR) ligand (obeticholic acid), PPAR α/δ agonist (elafibranor), thyroid β receptor agonist (resmetirom), and CCR2/5 antagonist (cenicriviroc) have entered phase 3 trials for NASH treatment.

• Obeticholic acid significantly improved hepatic fibrosis in NASH with stage 2/3 compared with placebo in an interim analysis of phase 3 REGENERATE study.

• Selective PPARα modulator, PPARδ agonist, PPARα/δ/γ agonist, non-bile acid FXR agonists, ACC inhibitors, SCD1 inhibitor, ketohexokinase inhibitor, direct AMPK activator, mitochondrial target of thiazolidinedione, recombinant pegylated FGF-21, FGF-19 agonist, ASBT inhibitor, SGLT1/2 inhibitor, GLP-1RA, pan-caspase inhibitor, toll-like receptor 4 antagonist, macrolide antibiotics, SSAO/VAP-1 inhibitor, IgG-rich extract of bovine colostrum from cows are expected for NASH treatment drugs, which have entered phase 2 trials for NASH treatment.

• Since NAFLD is the hepatic manifestation of the metabolic syndrome and considered as a multifactorial disease, it underscores the importance of combining therapies that engage different targets have synergistic benefit for individual therapies.

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Acknowledgments

This study was supported by members of Japan Study Group of NAFLD (JSG-NAFLD) at the department of research and development in Japan Strategic Medical Administration Research Center (J-SMARC).

Declaration of interest

Y Sumida has received honoraria from Mitsubishi Tanabe, Sumitomo Dainippon, AstraZeneca, Ono, and Taisho Pharmaceutical Ltd. Y Sumida has received research funding from Bristol-Meyers Squibb. M Yoneda has received honoraria from Mitsubishi Tanabe, Sumitomo Dainippon, Bristol-Myers Squibb, and Merck Sharp and Dohme. A Nakajima has received honoraria from Gilead, Bristol-Meyers Squibb, Novartis, and EA pharma. A Nakajima has also received research funding from EA Pharma, Mylan, and from Established Pharmaceuticals Division (EPD). This study was supported by members of the Japan Study Group of NAFLD (JSG-NAFLD) at the department of research and development at the Japanese Strategic Medical Administration Research Center (J-SMARC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.